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首页> 外文期刊>Cellular Signalling >Dishevelled stability is positively regulated by PKC zeta-mediated phosphorylation induced by Wnt agonists
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Dishevelled stability is positively regulated by PKC zeta-mediated phosphorylation induced by Wnt agonists

机译：通过WNT激动剂诱导的PKC Zeta介导的磷酸化积极调节折衷的稳定性

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Dishevelled (Dvl) proteins are central mediators of both canonical and non-canonical Wnt signaling. It is well known that, upon Wnt stimulation, Dvl becomes phosphorylated. However, how Wnt-induced phosphorylation of Dvl is regulated and its consequences are poorly understood. Here we found that Dvl proteins are overexpressed in colon cancer cells. In addition, we found that Wnt3a treatment rapidly induces hyperphosphorylation and stabilization of Dvl2 and Dvl3. The latter can be blocked by inhibition of Protein Kinase C (PKC)alpha, PKC delta, and PKC zeta isoforms. We also found that Wnt3a-induced phosphorylation of Dvl3 by PKC zeta is required to avoid Dvl3 degradation via proteasome. This demonstrated, to our knowledge for the first time, that hyperphosphorylation of Dvl by PKC zeta results in Dvl stabilization. This is clear contrast with the consequences reported to date of CK delta/epsilon-mediated Dvl phosphorylation upon Wnt treatment. Mapping the interaction domain between PKC zeta and Dvl3 indicated that, although the Dvl-DIX domain is required to stabilize PKCI;phosphorylated Dvl, it is not the region phosphorylated by this kinase. Our data show that the Dvl-DEP domain, required for specific interaction with PKC zeta, is the site phosphorylated by this kinase, and also probably the Dvl-C terminus. Our findings suggest a model of positive regulation of PKC zeta-mediated Dvl signaling activity, to produce a strong and sustained response to Wnt3a treatment by stabilizing Dvl protein levels.
机译：Dishaveled（Dvl）蛋白是典型和非典型Wnt信号的中心介体。众所周知，在Wnt刺激下，Dvl磷酸化。然而，Wnt诱导的Dvl磷酸化是如何调节的，其后果尚不清楚。我们发现Dvl蛋白在结肠癌细胞中过度表达。此外，我们发现Wnt3a处理可快速诱导Dvl2和Dvl3的过度磷酸化和稳定化。后者可通过抑制蛋白激酶C（PKC）α、PKCδ和PKC zeta亚型而被阻断。我们还发现Wnt3a诱导的PKC zeta对Dvl3的磷酸化是避免Dvl3通过蛋白酶体降解所必需的。据我们所知，这首次证明PKC zeta对Dvl的过度磷酸化导致Dvl稳定。这与迄今报道的Wnt治疗后CKδ/ε介导的Dvl磷酸化的结果形成了鲜明对比。绘制PKC zeta和Dvl3之间的相互作用域图表明，虽然稳定PKCI需要Dvl DIX结构域；磷酸化Dvl，它不是该激酶磷酸化的区域。我们的数据显示，与PKC zeta特异性相互作用所需的Dvl-DEP结构域是该激酶磷酸化的位点，也可能是Dvl-C末端。我们的研究结果表明，PKC zeta介导的Dvl信号活性的正调控模型，通过稳定Dvl蛋白水平，对Wnt3a治疗产生强烈而持续的反应。

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